Treatment of psychosis symptoms, for example schizophrenia (SCZ) symptoms with antipsychotics has been limited by poor efficacy and adverse reactions. This is especially true for second-generation antipsychotics, such as clozapine and olanzapine, where about 30% of treated patients experience significant weight gain. Antipsychotics are used to treat psychotic symptoms that are commonly observed in schizophrenia, bipolar disorder, and psychotic depression. They have been used increasingly to manage other psychiatric disorders, including bipolar manic and mixed episodes1, major depressive disorder2, 3, autistic spectrum disorder4, 5, general anxiety disorder, obsessive-compulsive disorder, dementia6-8.
While the underlying mechanisms of antipsychotic response and adverse effects remain unclear, genetic factors appear to play a prominent role9-14.
There is increasing evidence for a role of gamma-aminobutyric acid (GABA) in the regulation of food intake. GABA is produced in many regions of the brain, including the (proopiomelanocortin) POMC and Agouti-related peptide (AGRP) neurons in the hypothalamus15, 16. Diphtheria toxin-mediated ablation of GABA-secreting AGRP neurons induced an anorexic phenotype in mice (reviewed in17). Similarly, mice genetically deficient in GABA release from AGRP neurons were resistant to obesity induced by ghrelin18. The mechanism of this resistance could be through a decrease in food intake and an increase in energy expenditure in these AGRP GABA-deficient mice18. Conversely, administration of GABA agonists, including the benzodiazepine midazolam and L-838417, into the parabrachial nucleus in the brainstem, increased food intake19. Both GABAA and GABAB receptor agonists enhanced feeding in rodents and other animal models20-22. The GABRA2 gene, in particular, was one of the top findings in a recent genome-wide meta-analysis of obesity23, making it an appealing candidate gene for further investigation in obesity and related phenotypes.
There is also accumulating evidence for alterations in GABA neurotransmission by various antipsychotic drugs24-26. Clozapine and olanzapine, in particular, may exert their anxiolytic activity by increasing GABA-ergic neurotransmission27 through the allosteric action of neuroactive steroids including allopregnanolone at the GABAA receptor28. Olanzapine-induced weight gain and adiposity has been correlated to increased levels of the GABA synthesis enzyme GAD6529.
The GABRA2 gene (HGNC:4076), which is mapped to chromosomal region 4p12, codes for the GABAA receptor, alpha 2 subunit. While the GABRA2 gene was implicated in obesity23, it has not been investigated in relation to antipsychotic induced weight gain.
There is a need in the art for novel genetic markers. Further, there is a need in the art for novel genetic markers associated with antipsychotic-induced weight gain. Further, there is a need in the art for genetic diagnostic markers for antipsychotic-induced weight gain that provide physicians and other health care professionals with the opportunity to generate educated decisions for prescribing medications for treatment of psychosis. Moreover, there is a need in the art for personalized medicine approaches that lower the risk of developing antipsychotic induced weight gain and related ailments such diabetes and cardiovascular disease.